A predominant and limiting problem in the development and use of physiologically active agents is the inability to administer them as effectively as is desired. In particular, there is often a limitation as to the routes of administration because of the following factors:
(1) Some agents are inactivated in the gastrointestinal tract or they are absorbed poorly into the body from the tract. Also, undesirable side effects may result which prevent effective oral administration.
(2) In every case where injection must be resorted to, there is a risk of needle injury, infection and other trauma (including the emotional trauma inevitably associated with injections).
(3) Few agents are absorbed through the skin or mucous membranes in effective quantities and the rate of absorption is less than would be desirable for those that do.
(4) A local concentration for a local effect is often desired but a larger svstemic dose must be given to achieve an effective concentration at the local area when the agent can only be injected or given orally (but not topically). This higher dose often causes undesirable side effects, since dosage-related side effects are very prevalent for many agents.
Animal tissues comprise various membranes which are selectively permeable and which allow some substances to pass freely, while rejecting others or permitting only slight passage. Such membranes comprise the body coverings and externally communicating cavities, including the skin and mucous membranes of the body cavities, e.g. alimentary tract, respiratory tract, genitourinary tract, oral cavity, eyes, etc. (collectively defined herein as external membranes). They also include internal membranes such as the linings of the various organs and other internal body structures, e.g. peritoneum and pleura, and the membranes surrounding cellular and intracellular structures. It is desirable in overcoming the aforementioned problems in drug administration to increase the passage or penetration of agents across such membranes and further to enhance their intercellular and intracellular diffusion in order for them to reach their situs of activity more rapidly to achieve the desired response more quickly and often more effectively. It is exceptionally desirable to do this in a reversible manner, by which is meant penetration of the agents into tissue without adversely affecting or impairing the function or structure of the tissue. It is known that certain substances will penetrate tissue only after the tissue has been irreversibly damaged, which is certainly undesirable. Certain agents, such as surfactants, have been known previously for increasing penetration of various agents. However, again such penetration was effected only through irreversible damage of the tissue.
It has been a major rule in medicine that the "vehicles" or "carriers" have relatively little effect on the penetration rate for a given agent and this rule generally still holds true. Thus, with conventional carriers for medicines, such as alcohol, carbowax, water, etc., few agents will adequately penetrate such formidable external membrane barriers as the intact skin or mucous membrane. It is to be expected that this would be true of all potential "vehicles" or materials combined with physiologically active agents. However, surprisingly, it has been discovered that dimethyl sulfoxide (DMSO) has the unusual ability to greatly enhance the penetration of agents when they are applied to such membrane barriers along with dimethyl sulfoxide. The penetration of agents which previously have not penetrated these membranes to an effective degree may be enhanced sufficiently so that a useful result may be obtained. The penetration of agents which have been known to penetrate to a limited degree in conventional vehicles may be significantly enhanced. New and convenient routes of administration, often with a decrease in side effects of the agents, better localized concentration and a more sustained activity, may thereby be created for many agents.
In my co-pending application Ser. No. 615,377, filed Feb. 13, 1967, is disclosed my related discovery that DMSO enhances the penetration of plant-active agents (pesticides, dyes, nutrients, hormones, herbicides and the like) into plant tissue in a highly unusual manner.
Dimethyl sulfoxide is a water-white liquid at room temperature having a freezing point of approximately 18.5.degree. C. and a specific gravity of approximately 1.1. Dimethyl sulfoxide is a well known industrial solvent and it has been available in commercial quantities for at least a decade (from Crown Zellerbach Corporation, San Francisco, Calif.). DMSO was originally synthesized in 1866 and since that time it has been extensively investigated for possible industrial and biological utility and a considerable amount of literature has developed on its properties and uses. Over the last 25 years it has found widespread use as a solvent in industry and in the laboratory.
DMSO has been investigated in the past for various biochemical uses, for example as a reaction solvent for preparing derivatives of various proteins and antibiotics, as an extraction solvent for various proteins, as an analytical solvent and as a solvent for various other laboratory uses. It has also been suggested as a solvent for certain pesticides (see, for example, U.S. Pat. No. 3,068,142).
DMSO has been investigated as a preservative agent for in vitro storage of chilled or frozen tissue and it has also been determined to have a protective effect in experimental animals subjected to X-irradiation following injection of DMSO into such animals.
In connection with topical application of the antifungal griseofulvin, DMSO has been listed along with various inert materials as "bland, high boiling fluids" to be used as carriers for the griseofulvin in applying it to the skin to control fungus growth in the skin (see British Pat. No. 810,377). DMSO has been employed as a solvent for preparation of certain injectable formulations, namely chloramphenicol and an anthelminic preparation (see U.S. Pat. Nos. 3,044,936 and 3,067,096).
Despite the employment of DMSO as a solvent for these purposes and despite general experimentation with DMSO in the medical field, the unique ability of DMSO to alter membrane permeability and to thereby enhance penetration of physiologically active agents was neither suggested nor discovered. Although DMSO has been a well known and widely investigated solvent for many years, its unique ability to enhance penetration of external and internal membrane barriers as contemplated in the present invention has been totally unrecognized.
My co-pending application Ser. No. 753,231 is directed to utilizing DMSO to enhance penetration of various categories of physiologically active agents, including antineoplastic agents, antigens, antihistaminic agents, neuropharmacologic agents, diagnostic dyes and radiopaque agents and nutrients. Many of these categories are unrelated to steroids but some, such as antineoplastic agents and antiinflammatory agents, comprehend the various steroids having the indicated physiological activity. The present application is directed specifically to physiologically active steroids inclusive of those steroids having activities falling within the categories of my co-pending application and those that do not.